This invention relates to novel 3-alkyl-5-[(substituted amino)methyl]dihydro-3-phenyl-2(3H)-furanones and imino analogs thereof, and to the pharmaceutical compositions containing such compounds, that are useful as inhibitors of cardiac arrhythmias and are therefore useful in the treatment of irregular heartbeat. This invention also relates to the use of such compounds and pharmaceutical compositions in the treatment of irregular heartbeat. Some of the compounds of this invention also exhibit antihypertensive activity.
Arrhythmias are disorders relating to electrical impulse generation in the heart. The disorders include premature contractions (extrasystoles) originating in abnormal or ectopic foci in atria or ventricles; atrial flutter; atrial fibrillation; and ventricular tachycardia and fibrillation. For a discussion on these disorders, see, for example, L. S. Goodman and A. Gilman, eds., The Pharmacological Basis of Therapeutics; Sixth Edition, New York: Macmillan Publishing Co., 1980; pp. 761-767.
A number of compounds have been developed to alter cardiovascular function related to heart rate and rhythm. The cardiac glycosides, including digitalis, have as their main pharmacodynamic property the ability to increase the force of myocardial contraction. This positive inotropic action is the basis of the salutory effects of these cardiac glycosides in congestive heart failure--increased cardiac output; decreased heart size, venous pressure, and blood volume; and diuresis and relief of edema. Goodman and Gilman at pp. 730-731, 750-751. Quinidine is useful in the therapy of atrial fibrillation but exhibits several toxic reactions, such as cinchonism. Goodman and Gilman at pp. 768-774. Procaianmide acts in essentially the same manner as quinidine, and also exhibits toxic side effects. Goodman and Gilman at pp. 774-777. Lidocaine, a widely used local anesthetic, may be used in the treatment of ventricular arrhythmias, but must be administered by injection. Goodman and Gilman at pp. 779-781. Propranolol is useful in the treatment of supraventricular tachycardias and ventricular arrhythmias, but must be used with great care because it may induce significant hypotension, left ventricular failure, or even cardiovascular collapse. Goodman and Gilman at pp. 783-786. Disopyramide has effects somewhat like procainamide and quinidine, all being so-called Type 1 antiarrhythmics. At therapeutic levels disopyramide shortens the sinus node recovery time, lengthens the effective refractory period of the atrium, and has a minimal effect on the refractory period of the A-V node. Goodman and Gilman at pp. 777-779. However, because of the anticholinergic effects of some of the Type 1 antiarrhythmics, such as disopyramide, they should not be used in patients with glaucoma, myasthenia gravis, or problems of urinary retention.